The most important development in this field was the serendipitous discovery that sildenafil, a phosphodiesterase-5 (PDE-5) inhibitor, enhances erectile response.
There is now an extensive literature demonstrating the efficacy of sildenafil in erectile dysfunction treatment, which has been well reviewed by Rosen & McKenna (2002). They reviewed 12 controlled studies involving, together, more than 2500 men from around the world, and all using the International Index of Erectile Function as the principal outcome measure. In one study, a comparison was made with a sexually functional age-matched assoc control group (Dinsmore et al 1999). This showed that the men with erectile dysfunction increased their percentage of maximum response, as measured by the IIEF, from 34.2 % at baseline place to 72.6% with sildenafil, compared to 86.1% for the controls. It is difficult with most of these studies to establish what proportion of men failed to get a clinically useful response to treatment.
Meuleman et al (2001), however, reported that after 26 weeks of treatment 79 reported improved erections with sildenafil, and 27 with placebo. In most studies, there is evidence of dose-response effect, with available tablets of sildenafil containing 25,50 or 100 mg. The most common side effects are headache, flushing and dyspepsia, and they are also dose related. Two further PDE-5 inhibitors have been developed and are now in use: tadalafil (Cialis) and vardenafil (Levitra). Evidence of their effectiveness has been demonstrated (e.g. Padma-Nathan et al 2001 (tadalafil); Porst et al 2001; Fisher et al 2005 (vardenafil)) and they are both comparable to sildenafil in this respect.
The main differences between the three drugs are in their speed and duration of action. Sildenafil should be taken about 1 hour before sexual activity and has a half-life of around 3.5 hour. Tadalafil should be taken at least 30 minutes before sexual activity, and has a half-life of 17.5 hour; treatment effect can persist for 24-36 hour. Vardenafil is pharmacokinetically similar to sildenafil, but is more potent, with a dose range of 5-20 mg. These three compounds are similar in their side effects, though the duration of these relate to the half-life of the drug. One advantage of tadalafil is that its absorption is not delayed by food intake, which can be a problem with the other two. For all three drugs, the most important and dangerous drug interaction is with nitrates used for ischaemic heart disease, and this is a strong contraindication for the use of PDE-5 inhibitors. Most of the controlled outcome studies have used groups with mixed aetiologies for the erectile dysfunction, with the majority having an 'organic' component. Some studies have looked at groups with specific aetiologies. In men with diabetes, 60-65% show improvement of erectile function with PDE-5 inhibitors, which is lower than the outcome in typical mixed etiology groups but still better than placebo (Rendell et al 1999; Boulton et al 2001).
As yet no clear associations between treatment response and specific diabetic complications or glycaemic control have been reported. In men with ischaemic heart disease, around 70% have shown improvement in erectile function although side effects have been more frequent in these patients (Conti ek al 1999). In men with spinal cord injury, who typically have erectile dysfunction because of loss of neural activation of erection, results have been particularly good, with 80-88 % reporting improvement (Giuliano et al 1999 Sanchez et al 2001).
Several studies have assessed treatment in men with erectile dysfunction following prostatectomy, and overall the results have been disappointing, particularly in those men who have not received nerve-sparing surgery (reviewed by Rosen & McKenna 2002). Seidman et al found significant improvement in erectile function in men with erectile dysfunction who in addition reported untreated mild to moderate depression. They also found some associated improvement in mood and well-being that followed the improvement in erectile function. In spite of these impressive results from numerous placebo-controlled trials, the longer-term use of PDE-5 inhibitors appears to be limited.
In a recent large study in eight countries, of more than 25 000 men, aged 20-75 years, 16% were found to have erectile dysfunction. In a second phase, 1112 of the men identified with erectile dysfunction were followed up; 58% of them had sought medical help for the erectile dysfunction, but only 16% were currently using PDE-5 inhibitors (Rosen et al 141b). Various reasons were given for discontinuation, including lack of appropriate information from the physicians, fear of side effects, partner concerns and distrust of medications (Rosen 2007).
Leiblum (2002) has pointed out that the advantages of PDE-5 inhibitors may be less for men in relationships with chronic conflict or lack of desire in either partner. Such men are typically excluded from controlled treatment trials. Men with erectile dysfunction often have high expectations of success with PDE-5 inhibitors, having been influenced by the media 'hype' around these drugs. When the drug fails to work or loses its effect after initial success, it can be particularly devastating for the man (Tornlinson & Wright 2004).
Also, the reactions of the partner to a drug-induced erection aren't always favourable (Potts et al 2003).
The complex role of noradrenaline (NA) in sexual response was elaborated. NA transmission is largely responsible for the 'central arousal' component of sexual arousal, manifested by feelings of excitement and peripheral activation with increased blood pressure and heart rate. In the periphery, in contrast, NA is largely responsible for the inhibitory tone in erectile smooth muscle. Thus, increase in NA activity centrally is associated with arousal and decrease in NA activity peripherally with genital response.
A number of drugs influence NA transmission, though the receptors involved are complex. Drugs which antagonize pre-synaptic alpha2 receptors increase the amount of NA at the synapse, and hence enhance NA transmission. Drugs which antagonize post-synaptic alpha 1 receptors block NA mediated smoothe muscle contraction.
Yohimbine, originally derived from plants, is predominantly an alpha2 antagonist that has a long history as a putative aphrodisiac. A number of placebo-controlled trials of its use in the treatment of erectile dysfunction have been reported, but with various design deficiencies. Riley (1994), in reviewing this literature, concluded that yohimbine has a modest therapeutic benefit over placebo, and is generally well tolerated. In the early 1990s, a more specific alpha2 antagonist was developed by Syritex in the hope of maximizing the possible benefits of yohimbine. This compound, delequamine, was investigated in a series of laboratory studies, assessing both nocturnal penile tumescence (NPT) and erectile and cardiovascular responses to erotic stimuli, in men with and without erectile dysfunction.
The results were consistent with a central arousal enhancing effect, but this was only apparent in younger men with erectile dysfunction, raising the possibility that central NA arousal may be diminished with ageing. The results were also consistent with the idea that men with erectile dysfunction have increased alpha2 tone centrally, which reduces their capacity for central arousal in response to sexual stimuli. This compound did not make it through phase 3 studies, showing only modest effects. Phentolamine is an alpha1 and alpha2 antagonist used medically to treat hypertensive crises. It has been used, in combination with papaverine, to induce erection by intra-cavernosal injection.
In this case, the effect is presumably mediated by its alpha1 antagonist effect. In the penis, alpha2 receptors are found both pre- and post-synaptically. The post-synaptic alpha2 receptor probably has similar effects to the alpha1 receptor. In an earlier study, idazoxan, an alpha2 antagonist, had no effect when injected intracavernosally (Brindley 1984) probably because the pre- and postsynaptic effects cancelled each other out. The effects of phentolamine administered systemically are therefore of interest. Is it possible that it could improve sexual arousal by both blocking the peripheral alpha1 receptors and enhancing central arousal by blocking the alpha2 receptors in the brain? Goldstein et al (2001) reported two studies: one parallel group and the other crossover in design. In the parallel group study, significantly greater improvement in erectile response occurred with phentolamine than with placebo and was dose related. In the crossover study the differences were in the same direction but not significant. Long-term follow-up resulted in high attrition, but of those staying in the study, phentolamine continued to have beneficial effects. In a Mexican study (Ugarte et al 2002), sildenafil was found to be significantly more effective than phentolamine.
Given the central role of dopamine (DA) in both incentive motivation and central control of genital response, and the negative sexual effects of most DA antagonists, the effects of DA agonists are of obvious interest. However, the pharmacology of dopaminergic agents illustrates the complexity of the role of DA in the brain. DA antagonists may show their main sexual effect in reducing sexual interest. The main effects of dopamine agonists, like apomorphine, are to induce genital (i.e. erectile) response, probably via the oxytocinergic system (Heaton 2000). Cocaine and amphetamine, both drugs of addiction, increase DA activity either by inhibiting re-uptake (cocaine) or increasing release (amphetamine) of DA. These effects are presumably mediated via the incentive motivation system.
The pharmacological pursuit of DA-induced enhancement of sexual interest or response provides an interesting episode in the history of sexual pharmacology. In the 1980s Eli Lilly became the first pharmaceutical company to develop a drug specifically for this purpose, quinelorane, a D2 dopamine agonist. Extensive animal studies had shown its pro-sexual effects, including studies of primates (e.g. Pomerantz 1991). Phase 2 treatment studies in humans encountered substantial problems with side effects, mainly nausea and dizziness, leading to its abandonment clinically (Crenshaw & Goldberg 1996). I was involved in one of these controlled studies, and can recall one subject who developed a convincing erection but was unable to get off the bed because as soon as he lifted his head he would go round in circles.
The DA agonist that has received the most attention is apomorphine. Early studies, while showing positive effects on erection, also demonstrated substantial side effects (reviewed by Rosen 1991; Segraves 1995). The development of a sublingual route of administration (Apomorphine SL) was intended to lessen side effects by avoiding absorption via the liver. A number of studies have evaluated the effects of apomorphine SL in the treatment of erectile dysfunction.
In a placebo-controlled study of 296 men with erectile dysfunction, of mixed aetiology and severity, 3 mg of apomorphin SL was significantly better than placebo in improving erections; 4 mg was not more effective than the 3 mg dose but produced more side effects, nausea being the mo, frequent (Dula et al 2001). Similar results were reported in two European studies (Stief et al 2002; von Keitz et al 2002). Apomorphine SL is taken around 30 minutes before sexual activity. Although all of these studies, each funded by a pharmaceutical company, concluded that apomorphine was effective in the treatment of erectile dysfunction it is evident that nausea severely limits 'on-demand use, and only a minority of men have been willing to continue with the drug after completing the studies (Uckert et al 2006). Two further crossover studies have directly compared apomorphine SL with sildenafil: Eardley et al (2004) included men with erectile dysfunction who had not previously received pharmacological treatment for the problem, bui who had mixed aetiologies, and Perimenis et al (2004) included men diagnosed as having arteriogenic erectile dysfunction. Both studies showed a clear superiority of sildenafil over apomorphine. Perimenis et al (2004), whose study is unusual in focusing on a specific aetiology, pointed out that 20%, were not satisfied with either treatment.
The first human study relevant to treatment involved the use of melanotan-11, a non-selective melanocyte receptor agonist, administered subcutaneously (Wessells et al 2000). Subjects were monitored by Rigiscan for several hours following administration in their own home, and instructed to avoi deliberate sexual stimulation. This resulted in erections occurring in 17 out of 20 men with erectile dysfunction, and also an increase in sexual desire. But severe nausea in some men and a relatively long time before onset of action, around 2 h, limited the clinical value of this preparation.
Interest then shifted to bremelanotide (PT-141) a metabolite of melanotan-II, and a menalocortin analogue. In one placebo-controlled laboratory study (Diamond et al 2004), intranasal administration of PT-141 was found to enhance erections in response to visual sexual stimuli (VSS) in men with erectile dysfunction who had already found sildenafil to be effective. In a second study, using the same design but administering PT-141 subcutaneously and involving men with erectile dysfunction who had not responded to sildenafil, a similar positive effect on response to VSS was observed (Rosen et al 2004a). Side effects similar to those with apomorphine did occur, and were more marked in the second study, partly because of the higher plasma levels with subcutaneous than with intra-nasal administration, and also because the blood levels were sustained for longer. Vomiting, when it occurred, was 6-15 h after administration. The subcutaneous route had been used in the second study because it was anticipated that the erectile dysfunction subjects resistant to sildenafil would require higher plasma levels of PT-141. That proved not to be the case. Large scale phase 3 studies with this compound are underway at the time of writing.
The discovery that certain drugs injected into the corpus cavernosum induced erection was an important phase in the history of sexual medicine, and contributed to our understanding of erectile physiology. Whereas initially intracavernosal injection (ICI) was used as a method of investigation, it soon became a form of treatment by self-injection. The best established compound for ICI, and the only one approved for this purpose, is prostaglandin E1 (alprostadil or Caverject), a potent smooth relaxant and vasodilator. Erections occur within 5-20 min of the injection. The main side effect is penile pain, and the most serious is priapism. Any erection following ICI that lasts more than 4 h should be reported and dealt with medically.
Other compounds that have been used off-label for ICI are papaverine and phentolamine, an ocl and 2 adrenergic antagonist (see above) either separately or combined.
A preparation of alprostadil that is applied intraurethrally (MUSE) is available. In a direct comparison with ICl administration, the ICI was more effective and preferred (Shabsigh et al. 2000).
A new approach to the treatment of erectile dysfunction which is at a very early stage of development is gene therapy. The principles are complex (for a detailed overview see Gonzalez-Cadavid et al 2001). Much of the relevant work has been done by Melman and his colleagues, and in 2006 they reported their first, preliminary clinical results (Melman et al 2006). The key process in penile erection is relaxation of the smooth muscle of the corpora cavernosa and also penile arterial walls. At the cellular level this complex process involves the balance of potassium (K') outflow and calcium (Ca 21) influx, with maintenance of smooth muscle contractile tone depending on a sufficient concentration of Ca . In response to signals intended to produce erection, the K' channels open, resulting in an outflow of K' and hyperpolarization that limits Ca 2+ entry. The focus of Melman's approach is to produce an increased expression of K+ channel genes, which are believed to be reduced by ageing or disease processes like diabetes. They have developed a 'naked' DNA plasmid that they call hMaxi-K, which is administered by singledose intracavemosal injection. The hope is not only to enhance erectile response but to do so for a relatively long period (several months). So far such injections have not resulted in any adverse effects. In their first clinical report, in which varying doses of the gene were administered to 11 men, 2 out of the 11 reported improved erectile function, which was maintained through the 24 weeks of the study. The two responders were among the five receiving the higher doses of the gene plasmid. Interestingly, one of the two responders was not only the youngest in the group (aged 42) but also the only one to be diagnosed as having psychogenic erectile dysfunction. Obviously, further studies are required before the therapeutic potential of this approach can be evaluated.
The medicalization of sexual problems
Male sexual dysfunction, mainly erectile, attracted the interest of surgeons in the 1930s (Johnson 1968). That was a passing phase. For some years after that, the prevailing wisdom was that erectile dysfunction was 90% psychological in its origins, though apart from psychoanalysis, which was of limited relevance, psychological treatments were not available. Things changed in the 1970s. On the one hand, Masters & Johnson (1970) started a new era of psychologically-based therapy for sexual problems. On the other hand, urological and vascular surgeons re-entered the field. We will be considering Masters and Johnson's treatment approach in the next chapter. The surgical approaches initially focused on the penis (and not the man attached to it), with various types of penile implant to provide a relatively permanent erection, or vacuum devices to induce an erection followed by tight bands at the base of the penis to prevent loss of an erection once established. With technological development, implants became more sophisticated, involving a small pump implanted into the scrotum that allowed the man to inflate the implant when needed. Alongside these surgical treatments a veritable diagnostic industry emerged. Men are sufficiently troubled by impotence that they will pay to get it sorted out. Given that the surgical methods of treatment were mostly irreversible, reducing if not eliminating the possibility of a return of normal erectile function, the approach was to demonstrate the 'organic' (hence irreversible) nature of the erectile problem. Two types of diagnostic procedure were used.
The first was used to distinguish between 'organic' and 'psychogenic' problems; initially the principal method used was measurement of nocturnal penile tumescence with the occurrence of relatively normal NPT taken as evidence of psychogenicity and the lack of normal NPT as indicating an 'organic' problem. The second type of procedure focused on specific aetiologies of 'organic' impotence, in particular vascular and neurological abnormalities. In the 1980s a new and important dimension was added. It was discovered that injection of smooth muscle relaxants into the corpora cavernosa would typically induce erection, This initially was used for diagnostic purposes, the assumption being that such injections were assessing the peripheral mechanisms of erection and not their control by the brain. Soon intracavernosal injections became widely used as a form of treatment.
This phase of intensive diagnostic investigation did result in a substantial amount of new knowledge about erectile function and dysfunction and the cause of erection problems. In terms of diagnosis relevant to treatment, however, it was flawed because of the assumption that the penis could be investigated independently of the man attached to it. It soon became apparent, for example, that psychogenic factors could suppress the erectile response to intracavernosal injections (Granata et al 1995). NPT is suppressed in states of depression, which do not involve malfunctioning of the genital response system but rather a depression related reduction in central excitatory tone. Men with vascular impairment could have a substantial worsening of any erectile dysfunction as a result of psychological reactions to the basic impairment. In other words, the relationship between the man and his penis had been largely ignored in this phase of medicalization.
The next phase followed the introduction of Viagra in the late 1990s. This is effective in inducing erection in around two-thirds of men with erectile dysfunction, but it is noteworthy that the long-term use of this medication is uncertain, and side effects are not trivial. The relevance to this discussion is that, until recently, very little attempt has been made to assess the impact of drugs like Viagra on the sexual relationship, or on the partner (Rosen et al 2006 report a pilot study). The impact of an expensive drug (not usually covered by health insurance), that enhances erectile response for several hours, may impose a 'sexuality' on the relationship which is not necessarily welcomed by the partner, and this may be particularly relevant to older age groups.
There is a clear distinction between sexual arousal and orgasm/ejaculation in male sexual response. Penile erection is a tangible and crucial component of a man's experience of sexual arousal. The awareness of an erection not only signifies the sexual nature of central processes, but also acts as a powerful stimulant in the psychosomatic circle, further enhancing the arousal process. The lack of erection therefore has a significant negative effect in a situation where sexual arousal is wanted. This underlines the psychosomatic nature of erectile dysfunction. Whether or not there are peripheral explanations for impaired erection (e.g. vascular disease), the man's reaction will play a large part in how problematic the erectile impairment becomes. Hence we see an interaction between personality related psychological processes and peripheral physiological mechanisms. This has commonly been conceptualized as 'performance anxiety', though there is a striking lack of research on this component of male sexual dysfunction. We considered three central response patterns, each of which may be clinically relevant, although probably varying in importance across individuals: first, distraction from the sexual stimuli due to concerns about performance failure, second, insufficient reduction of inhibitory tone and, third, reactive inhibition in response to a negative appraisal of the situation. Further research may tell us whether these three patterns can be distinguished clinically. At this juncture, however, we can consider erectile difficulty as one type of male sexual problem, leaving the clinician with the need to weigh the relative importance of physical and psychological factors in each case. Erectile problems vary in severity; in some men the problem only occurs on a proportion of occasions of sexual activity. The problem may be a failure to sustain the erection after vaginal entry, some degree of erection but insufficient rigidity of erection to allow vaginal entry, or minimal or no erectile response. Variable degrees of erection with a tendency to lose erection when vaginal entry is being attempted is suggestive of inhibition being involved, with concern about performance having an adverse effect. A more or less complete absence of erectile response is suggestive of a basic failure of the erectile mechanism (e.g. from vascular or neurological impairment).
Erectile dysfunction: diagnosis and treatment
Erectile dysfunction and ageing
Erectile dysfunction and diabetes, ED and hypertension
Click here for more information on premature ejaculation.